Alzheimer's disease (AD) is commonly associated with a family history; 40% of patients with AD have at least one other afflicted first-degree relative. Numerous genes have been associated with late-onset Alzheimer's disease (AD), while mutations in chromosomes 1, 14, and 21 have been associated with early onset familial AD.

Susceptibility Polymorphism at the Apolipoprotein E (APOE) Gene

The APOE lipoprotein is a carrier of cholesterol produced in the liver and brain glial cells. The APOE gene has 3 alleles—epsilon 2, 3, and 4—with the epsilon 3 allele being the most common. Every person carries two APOE alleles. The presence of at least 1 epsilon 4 allele is associated with an increased risk of AD in the range of 1.2- to 3-fold, depending on the ethnic group. For those homozygous for epsilon 4 (about 2% of the population), the risk of AD is higher than for those heterozygous for epsilon 4. The mean age of onset of AD is about 68 years for epsilon 4 homozygotes, about 77 years for heterozygotes, and about 85 years for those with no epsilon 4 alleles. About half of patients with sporadic AD carry an epsilon 4 allele. However, not all patients with the allele develop AD. It should be noted that the epsilon 4 allele represents a risk factor for AD rather than a disease-causing mutation. In the absence of APOE testing, first-degree relatives of an individual with sporadic or familial AD are estimated to have a 2- to 4-fold greater risk of developing AD than the general population. There is evidence of possible interactions between epsilon 4 alleles, other risk factors for AD (eg, risk factors for cerebrovascular disease such as smoking, hypertension, hypercholesterolemia, diabetes), and a higher risk of developing AD. However, it is not clear that all risk factors have been taken into account in such studies, including the presence of polymorphisms in other genes that may increase the risk of AD.

Recent studies identified rs75932628-T, a rare functional substitution for R47H of TREM2, as a heterozygous risk variant for late-onset AD. On chromosome 6p21.1, at position 47 (R47H), the T allele of rs75932628, encodes a histidine substitute for arginine in the gene that encodes TREM2.

TREM2 is highly expressed in the brain and is known to have a role in regulating inflammation and phagocytosis. TREM2 may serve a protective role in the brain by suppressing inflammation and clearing it of cell debris, amyloids and toxic products. A decrease in the function of TREM2 would allow inflammation in the brain to increase and may be a factor in the development of AD. The effect size of the TREM2 variant confers a risk of AD that is similar to the APOE epsilon 4 allele, although it occurs less frequently.

Genetic Mutations

Patients with early onset AD (i.e., before age 65 but as early as 30 years) are a small subset of patients. The families of these patients may show an autosomal dominant pattern of inheritance. Three genes have been identified by linkage analysis of affected families: amyloid-beta precursor protein gene (APP), presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene. APP and PSEN1 mutations have 100% penetrance absent death from other causes, while PSEN2 has 95% penetrance.A variety of mutations within these genes has been associated with AD; mutations in PSEN1 appear to be the most common. While only 3%–5% of all patients with AD have early onset disease, pathogenic mutations have been identified in up to 70% or more of these patients. Therefore, overall, identifiable genetic mutations are rare causes of AD.

Testing for the APOE 4 allele in patients with late-onset AD and for APP, PSEN1, or PSEN2 mutations in the rare patient with early-onset AD have been investigated as an aid in diagnosis in patients presenting with symptoms suggestive of AD, or as a technique for risk assessment in asymptomatic patients with a family history of AD. Mutations in PSEN1 and PSEN2 are specific for AD; APP mutations are also found is cerebral hemorrhagic amyloidosis of the Dutch type, a disease in which dementia and brain amyloid plaques are uncommon.

Diagnosis of AD

The diagnosis of AD is divided into three categories: possible, probable, and definite AD.The diagnosis of definite AD requirespostmortem confirmation of AD pathology, documenting the presence of extracellular beta amyloid plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. As a result, a diagnosis of definite AD cannot be made during life, and the diagnosis of probable or possible AD is made on clinical grounds. Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. Criteria for diagnosis of probable AD have been developed by the National Institute on Aging and the Alzheimer’s Association. These criteria require evidence of a specific pattern of cognitive impairment, a typical clinical course, and exclusion of other potential etiologies, as follows:

Cognitive impairment

Cognitive impairment established by history from patient and a knowledgeable informant, plus objective assessment by bedside mental status examination or neuropsychological testing

Cognitive impairment involving a minimum of 2 of the following domains:

Impaired ability to acquire and remember new information

Impaired reasoning and handling of complex tasks, poor judgment

Impaired visuospatial abilities

Impaired language functions

Changes in personality, behavior, or comportment

Initial and most prominent cognitive deficits are one of the following:

Amnestic presentation

Nonamnestic presentations, either a language presentation with prominent word-finding deficits; a visuospatial presentation with visual cognitive defects; or a dysexecutive presentation with prominent impairment of reasoning, judgment, and/or problem solving.

Clinical course

Insidious onset

Clear-cut history of worsening over time

Interference with ability to function at work or usual activities

Decline from previous level of functioning and performing

Exclusion of other disorders

Cognitive decline not explained by delirium or major psychiatric disorder

No evidence of other active neurologic disease, including substantial cerebrovascular disease or dementia with Lewy bodies.

Lack of prominent features of variant frontotemporal dementia or primary progressive aphasia.

No medication use with substantial effects on cognition.

A diagnosis of possible AD dementia is made when the patient meets most of the AD criteria, but has an atypical course or an etiologically mixed presentation. This may consist of an atypical onset (eg, sudden onset) or atypical progression. A diagnosis of possible AD is also made when there is another potentially causative systemic or neurologic disorder that is not thought to be the primary etiology of dementia.

Mild cognitive impairment (MCI) is a precursor of AD in many instances. MCI may be diagnosed when there is a change in cognition, but not sufficient impairment for the diagnosis of dementia. Features of MCI are evidence of impairment in one or more cognitive domains and preservation of independence in functional abilities. In some patients, MCI may be a predementia phase of AD. Patients with MCI may undergo ancillary testing (eg, neuroimaging, laboratory studies, neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors.

No U.S. Food and Drug Administration (FDA)‒cleared genotyping tests were found. FDA has not regulated these tests to date. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act.

Genetic testing for the diagnosis or risk assessment of Alzheimer's disease is considered investigational. Genetic testing includes, but is not limited to, testing for the apolipoprotein E epsilon 4 allele, presenilin genes, amyloid precursor gene, or TREM2.

Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.